Bundle-specific associations between white matter microstructure and Aβ and tau pathology in preclinical Alzheimer's disease

  1. Alexa Pichet Binette  Is a corresponding author
  2. Guillaume Theaud
  3. François Rheault
  4. Maggie Roy
  5. D Louis Collins
  6. Johannes Levin
  7. Hiroshi Mori
  8. Jae Hong Lee
  9. Martin Rhys Farlow
  10. Peter Schofield
  11. Jasmeer P Chhatwal
  12. Colin L Masters
  13. Tammie Benzinger
  14. john Morris
  15. Randall Bateman
  16. John CS Breitner
  17. Judes Poirier
  18. Julie Gonneaud
  19. Maxime Descoteaux
  20. Sylvia Villeneuve  Is a corresponding author
  21. for the DIAN Study Group and the PREVENT-AD Research Group
  1. McGill University, Canada
  2. Université de Sherbrooke, Canada
  3. Montreal Neurological Institute and Hospital, Canada
  4. Ludwig-Maximilians-Universität München, Germany
  5. Osaka City University Medical School, Japan
  6. University of Ulsan College of Medicine, Asan Medical Center, Republic of Korea
  7. Indiana University, United States
  8. Neuroscience Research Australia, Australia
  9. Harvard Medical School, Massachusetts General Hospital, United States
  10. University of Melbourne, Australia
  11. Washington University School of Medicine, United States

Abstract

Beta-amyloid (Aβ) and tau proteins, the pathological hallmarks of Alzheimer's disease (AD), are believed to spread through connected regions of the brain. Combining diffusion imaging and positron emission tomography, we investigated associations between white matter microstructure specifically in bundles connecting regions where Aβ or tau accumulates and pathology. We focussed on free-water corrected diffusion measures in the anterior cingulum, posterior cingulum, and uncinate fasciculus in cognitively normal older adults at risk of sporadic AD and presymptomatic mutation carriers of autosomal dominant AD. In Aβ-positive or tau-positive groups, lower tissue fractional anisotropy and higher mean diffusivity related to greater Aβ and tau burden in both cohorts. Associations were found in the posterior cingulum and uncinate fasciculus in preclinical sporadic AD, and in the anterior and posterior cingulum in presymptomatic mutation carriers. These results suggest that microstructural alterations accompany pathological accumulation as early as the preclinical stage of both sporadic and autosomal dominant AD.

Data availability

All raw imaging data from PREVENT-AD is openly available to researchers on the data repository https://registeredpreventad.loris.ca/

The following data sets were generated
    1. Tremblay-Mercier et al.
    (2021) PREVENT-AD
    LORIS Repository, 10.5281/zenodo.4535262.

Article and author information

Author details

  1. Alexa Pichet Binette

    Psychiatry, McGill University, Montreal, Canada
    For correspondence
    alexa.pichetbinette@mail.mcgill.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5218-3337
  2. Guillaume Theaud

    Computer Science, Université de Sherbrooke, Sherbrooke, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. François Rheault

    Computer Science, Université de Sherbrooke, Sherbrooke, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Maggie Roy

    Computer Science, Université de Sherbrooke, Sherbrooke, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. D Louis Collins

    McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal Neurological Institute and Hospital, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8432-7021
  6. Johannes Levin

    Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Hiroshi Mori

    Clinical Neuroscience, Osaka City University Medical School, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  8. Jae Hong Lee

    Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  9. Martin Rhys Farlow

    Neurology, Indiana University, Bloomington, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Peter Schofield

    Faculty of Medicine, Neuroscience Research Australia, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Jasmeer P Chhatwal

    Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Colin L Masters

    University of Melbourne, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  13. Tammie Benzinger

    Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. john Morris

    Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Randall Bateman

    Neurology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. John CS Breitner

    Psychiatry, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  17. Judes Poirier

    Psychiatry, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  18. Julie Gonneaud

    Psychiatry, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  19. Maxime Descoteaux

    Computer Science, Université de Sherbrooke, Sherbrooke, Canada
    Competing interests
    The authors declare that no competing interests exist.
  20. Sylvia Villeneuve

    Psychiatry, McGill University, Montreal, Canada
    For correspondence
    sylvia.villeneuve@mcgill.ca
    Competing interests
    The authors declare that no competing interests exist.

Funding

Canadian Institutes of Health Research (PJT-162091)

  • Sylvia Villeneuve

Canadian Institutes of Health Research (PJT- 148963)

  • Sylvia Villeneuve

Levesque Foundation

  • Judes Poirier

Douglas Hospital Research Centre and Foundation

  • John CS Breitner

Canada Foundation for Innovation

  • Sylvia Villeneuve

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The study was approved by the ethics committee of the Faculty of Medicine of McGill University and of the Douglas Mental Health University Institute. Informed consent was obtained from all PREVENT-AD and DIAN participants prior to enrolling in the respective studies.We had access to the DIAN data with approval from DIAN leaders (data request DIAN-D1624).

Reviewing Editor

  1. Morgan Barense, University of Toronto, Canada

Publication history

  1. Received: September 9, 2020
  2. Accepted: May 12, 2021
  3. Accepted Manuscript published: May 13, 2021 (version 1)
  4. Version of Record published: June 1, 2021 (version 2)

Copyright

© 2021, Pichet Binette et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Alexa Pichet Binette
  2. Guillaume Theaud
  3. François Rheault
  4. Maggie Roy
  5. D Louis Collins
  6. Johannes Levin
  7. Hiroshi Mori
  8. Jae Hong Lee
  9. Martin Rhys Farlow
  10. Peter Schofield
  11. Jasmeer P Chhatwal
  12. Colin L Masters
  13. Tammie Benzinger
  14. john Morris
  15. Randall Bateman
  16. John CS Breitner
  17. Judes Poirier
  18. Julie Gonneaud
  19. Maxime Descoteaux
  20. Sylvia Villeneuve
  21. for the DIAN Study Group and the PREVENT-AD Research Group
(2021)
Bundle-specific associations between white matter microstructure and Aβ and tau pathology in preclinical Alzheimer's disease
eLife 10:e62929.
https://doi.org/10.7554/eLife.62929

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